The goal of this project is to correlate hepatic microsomal enzyme induction and tolerance to lethality as a result of multiple oral administration of d,1-methadone, 1-acetylmethadol and d-propoxyphene in the mouse, rat, dog and monkey. Both in vivo and in vitro microsomal enzyme parameters will be employed to obtain information on the relative microsomal enzyme inducibility, especially temporal aspects (decay rate of induced enzyme activity) and enzyme specificity, by the three maintenance agents. In addition, single oral LD50's will be determined in naive animals and in animals treated with an inducing dose of the above agents to quantitate the degree of tolerance to lethality rendered. On the basis of these results, an animal model will be chosen which closely simulates the primate work with respect to relative toxicities and induction of specific microsomal enzyme activities. It is hoped that this model will serve to predict possible drug interactions arising from the respective maintenance agents and commonly used drugs.